Glioblastoma multiforme (GBM) is a devastating form of primary brain cancer with poor prognosis. GBM cells are heterogeneous containing a subpopulation of glioma stem cells (GSCs)-, chemo- and radiotherapy resistant cells with prominent tumorigenic ability, and non- GSCs. Here, we propose a novel concept for the significance of non-GSCs for GBM stemness - irradiation triggers paradoxical signals from apoptotic signals in non-GSCs to induce an inter-cellular proliferative signal in the neighboring GSCs, rendering them hyper- proliferative and therapy-resistant GSCs in GBM. This hypothesis is based on the elegant studies in Drosophila eye cancer models demonstrating that inter-clonal cooperation and signaling from apoptotic clones provoke aggressive growth of neighboring tumorigenic clones. These aggressive tumors show up-regulation of JNK (upstream of c-JUN), Dronc (Drosophila Casp9) and Wg (Drosophila Wnt). Our preliminary data suggests that, even in human cancers, c-JUN (and its binding partner MELK), Caspase 9, and Wnt likely contribute to the hyper-proliferation in aggressive tumors. Given the importance of Wnt in the CNS development and self- renewal of stem cells, we hypothesize that, similar to the Drosophila cancer models, induction of apoptosis in non-GSCs drives compensatory proliferation of GSCs through Wnt activation in humans. We propose to study the inter-cellular interactions between the apoptosis-prone non-GSC cells and the hyper-proliferative GSCs using the in vitro tumor sphere cultures and xenograft based mammalian models. As the proof-of-principal and for the clinical development, we will then test the efficacy of the MELK inhibitor and the WNT inhibitor, both of which were currently tested by Phase I Clinical Trial for advanced non-CNS cancers. We believe that this co- clinical trial approach will guide us to design successful Phase II/III trils for clinical use of novel anti-cancer drugs. Overall, our research is novel because the conceptual idea that the dying non-GSCs secrete signals that induce proliferation of GSCs is promising and untested. Our approaches and investigation will yield insights about molecular signaling interactions in the context of post-irradiation management of GBM, and is likely to revise our understanding of changes in gene expression and cell-cell interactions post-irradiation, which is a vital area of cancer biology with wide-applications to many cancer types.